Fludarabine Phosphate, Low-Dose Total-Body Radiation Therapy, and Peripheral Blood Stem Cell Transplant Followed By Donor Lymphocyte Infusion in Treating Older Patients With Chronic Myeloid Leukemia
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Purpose
Patients are asked to take part in this study because they have been diagnosed with Chronic Myeloid Leukemia. Chronic myelogenous leukemia (CML) is a disease for which the only proven cure is by treatment that includes bone marrow transplantation. This study will test the use of a new approach to transplants for CML that uses lower doses of radiation for treatment. Studies in patients who have relapsed with CML after a bone marrow transplant have shown that further infusion of cells collected from the donor's blood (donor leukocyte infusions or DLI) is able to produce prolonged disease remissions in a high proportion of patients including cases where there is no detectable leukemia by the most sensitive techniques available. This is evidence for an immune attack on the leukemia by the donor cells. This effect is known as a graft-versus-leukemia (GVL) effect, and this appears to be a powerful form of treatment for CML. The goal of this study is to utilize this GVL effect against CML in an attempt to kill the patients' leukemia cells without using the usually toxic high-dose transplant chemotherapy or radiation which is responsible for many of the side effects of transplantation
| Condition | Intervention | Phase |
|---|---|---|
|
Accelerated Phase Chronic Myelogenous Leukemia Childhood Chronic Myelogenous Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Phase Chronic Myelogenous Leukemia Relapsing Chronic Myelogenous Leukemia |
Drug: fludarabine phosphate Drug: cyclosporine Drug: mycophenolate mofetil Procedure: peripheral blood stem cell transplantation Radiation: total-body irradiation Biological: therapeutic allogeneic lymphocytes Other: laboratory biomarker analysis Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Induction Of Mixed Hematopoietic Chimerism Using Fludarabine, Low Dose TBI , PBSC Infusion And Post-Transplant Immunosuppression With Cyclosporine And Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion In Patients With Chronic Myeloid Leukemia in Chronic and Accelerated Phases: A Multi-Center Study. |
- Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality [ Time Frame: Within the first 65 days ] [ Designated as safety issue: Yes ]All unexpected toxicities will be summarized and reported.
- Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed [ Time Frame: Day 28 ] [ Designated as safety issue: No ]Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.
- Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed [ Time Frame: Day 56 ] [ Designated as safety issue: No ]Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.
- Proportion of patients experiencing a complete antileukemic response [ Time Frame: At 12 weeks after the final DLI ] [ Designated as safety issue: No ]
- Proportion of patients experiencing GVHD [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
- Proportion of patients experiencing non-relapse mortality [ Time Frame: Within 65 days of transplant ] [ Designated as safety issue: Yes ]
- Incidence of myelosuppression after initial PBSC infusion [ Time Frame: Until 2 months post-transplant ] [ Designated as safety issue: Yes ]
- Incidence of aplasia after DLI [ Time Frame: Until 2 months post-transplant ] [ Designated as safety issue: Yes ]
- Incidence of grades 2-4 acute GVHD after DLI [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
- Incidence of grades 2-4 acute GVHD after PBSC infusion [ Time Frame: Until day 90 after the last DLI ] [ Designated as safety issue: Yes ]
- Incidence of grades chronic extensive GVHD after DLI [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]
- Dose of CD3+ cells required to convert mixed to full lymphoid chimeras [ Time Frame: Day 56 ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 20 |
| Study Start Date: | August 1997 |
| Primary Completion Date: | March 2005 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (chemotherapy, TBI, PBSCT, DLI)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV BID or TID on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27. DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor CD3+ T cells and no evidence of GVHD receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD. |
Drug: fludarabine phosphate
Given IV
Other Names:
Drug: cyclosporine
Given PO or IV
Other Names:
Drug: mycophenolate mofetil
Given PO or IV
Other Names:
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSCT
Other Names:
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Biological: therapeutic allogeneic lymphocytes
Given IV
Other Name: ALLOLYMPH
Other: laboratory biomarker analysis
Correlative studies
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSCT
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To determine if mixed hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen in patients > 65 years of age with CML in chronic or accelerated phase who have human leukocyte antigen (HLA) identical related donors.
II. To determine if mixed chimerism, established with non-myeloablative conditioning regimens, can be converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI), and thereby produce an immunologic cure of the malignancy.
OUTLINE:
CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo low-dose total-body irradiation (TBI) on day 0.
TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV BID or thrice daily (TID) on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27.
DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor cluster of differentiation (CD)3+ T cells and no evidence of graft-versus-host disease (GVHD) receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD.
After completion of study treatment, patients are followed up periodically for 5 years.
Eligibility| Ages Eligible for Study: | up to 74 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic and first accelerated phases
- Patients =< 65 years old who are at high risk of regimen related toxicity through pre-existing chronic disease affecting liver, lungs, and/or heart, or others who wish to be treated on this protocol, will be considered on a case-by-case basis; transplants should be approved for these inclusion criteria by both the participating institutions' patient review committees such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators at the collaborating centers; patients =< 65 years of age who have received previous high-dose transplantation do not require patient review committee approvals; all children < 12 years must be discussed with the FHCRC principal investigator (PI) (Brenda Sandmaier, MD 206-667-4961) prior to registration
- HLA genotypically identical related donor willing to undergo leukapheresis initially for collection of peripheral blood stem cell (PBSC) and subsequently for collection of peripheral blood mononuclear cell (PBMC)
- Patients treated with alpha interferon must have discontinued drug at least 1 month prior to transplant
- DONOR: HLA genotypically identical family member (excluding identical twins)
- DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
- DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
Exclusion Criteria:
- GROUP 1: (PATIENTS AGED > 65 AND < 75 YEARS)
- Patients who are human immunodeficiency virus positive (HIV+)
- Patients unwilling to use contraceptive techniques during and for 12 months following treatment
- Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML
- Patients in an interferon induced complete or partial cytogenetic remission
Organ dysfunction:
- Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
- Cardiac ejection fraction < 40%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted
- Liver function tests including total bilirubin, serum glutamic pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2x the upper limit of normal unless proven to be due to the malignancy
- Karnofsky score < 70
- Patients with poorly controlled hypertension
- GROUP 2 (PATIENTS AGED =< 65)
- Patients who are HIV+
- Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML
- Females who are pregnant
- Patients unwilling to use contraceptive techniques during and for 12 months following treatment
- Patients in an interferon induced complete or partial cytogenetic remission
Organ dysfunction:
- Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels
- Cardiac ejection fraction < 40% or a history of congestive heart failure; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
- Severe defects in pulmonary function testing as defined by the pulmonary consultant (defects are currently categorized as mild, moderate and severe) or receiving supplementary continuous oxygen; DLCO < 50% of predicted
- Liver function tests: total bilirubin > 2x the upper limit of normal, SGPT and SGOT 4x the upper limit of normal
- Karnofsky score < 50
- Patients with poorly controlled hypertension
- DONOR: Age less than 12 years
- DONOR: Pregnancy
- DONOR: Infection with HIV
- DONOR: Inability to achieve adequate venous access
- DONOR: Known allergy to G-CSF
- DONOR: Current serious systemic illness
Contacts and Locations| United States, California | |
| City of Hope Medical Center | |
| Duarte, California, United States, 91010 | |
| Stanford University | |
| Stanford, California, United States, 94305 | |
| United States, Colorado | |
| University of Colorado | |
| Denver, Colorado, United States, 80217 | |
| United States, Texas | |
| Baylor University Medical Center | |
| Dallas, Texas, United States, 75246 | |
| United States, Washington | |
| Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | |
| Seattle, Washington, United States, 98109 | |
| VA Puget Sound Health Care System | |
| Seattle, Washington, United States, 98101 | |
| Germany | |
| Universitaet Leipzig | |
| Leipzig, Germany, D-04103 | |
| Italy | |
| University of Torino | |
| Torino, Italy, 10126 | |
| Principal Investigator: | Brenda Sandmaier | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium |
More Information
No publications provided
| Responsible Party: | Sandmaier, Brenda, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium |
| ClinicalTrials.gov Identifier: | NCT00003145 History of Changes |
| Other Study ID Numbers: | 1209.00, NCI-2012-00579, P01CA018029, P01CA078902 |
| Study First Received: | November 1, 1999 |
| Last Updated: | April 19, 2013 |
| Health Authority: | United States: Federal Government |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Accelerated Phase Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Chronic-Phase Neoplasms by Histologic Type Neoplasms Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Cyclosporins Cyclosporine Mycophenolic Acid Mycophenolate mofetil Fludarabine monophosphate |
Vidarabine Fludarabine Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antifungal Agents Anti-Infective Agents Therapeutic Uses Dermatologic Agents Antirheumatic Agents Antibiotics, Antineoplastic Antineoplastic Agents |
ClinicalTrials.gov processed this record on May 19, 2013